Very low birth weight [VLBW] infants have an increased risk of brain injury [BI] and consequently, are more likely to exhibit signs of motor, cognitive, or behavioral impairment. Studies have examined the effects of Apolipoprotein E (APOE) genotype on outcomes after BI, primarily in adults. The APOE gene has three variants [e2, e3, and e4] and encodes the apoE protein involved in cholesterol and lipid transport in the central nervous system [CNS]. While the presence of the APOE e4 allele is associated with a worse neurological outcome in adults, initial studies have indicated that APOE e4 protects the developing brain in children after BI. In this prospective study, APOE genotype will be ascertained by analysis of DNA obtained by buccal swab for150 consecutive infants admitted to NICU with birth weight less than 1000 gm. Brain MRI will be obtained on each subject at term equivalent. Neurodevelopment will be assessed by a standardized neurological protocol and the Bayley-III exam at twelve months corrected age. This exploratory study's aims are to demonstrate that APOE e4, in contrast to e2 or e3, is associated with better neurodevelopmental outcomes at 12 months;that APOE e4 has a mitigating effect on intracerebral hemorrhage, periventricular leukomalacia, and cerebral atrophy;and that APOE genotype effects vary at different gestational ages and birth weights. The results of this study could lead to a clinical trial of an apoE e4 protein isoform for very premature infants with or at high risk for brain injury. PUBLIC HEALTH RELEVANCE: Brain injury (BI) due to various causes and mechanisms in the peri- or neonatal period remains a major determinant of long-term mental and physical disability. While research attention has been appropriately directed towards prevention of BI, such as that caused by intraventricular hemorrhage (IVH), fewer successes in reducing the impact of BI have been demonstrated, with the possible exception of brain cooling after perinatal asphyxia. We propose an exploratory research project to demonstrate that the e4 allele of the Apolipoprotein E (APOE) gene is associated with better outcomes after early BI than either the e2 or e3 alleles. If so, this could lead to a clinical trial of administration of an e4 protein isoform in the acute setting. Success in such a trial could provide a radically new and innovative approach to acute treatment of BI in newborns.